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A new siderophore, serratiochelin D (1), was isolated from a soil-derived, non-pigmented strain of Serratia marcescens along with two previously reported siderophores, serratiochelins A and B. Siderophores were obtained after cultivating the bacterium in an iron-deficient medium, and the chemical structures were elucidated based on HPLC-UV, mass spectrometry, and extensive 1D and 2D NMR spectral analyses. The iron-chelating, growth-promoting, and cytotoxic activities were evaluated using standard methods. Serratiochelin D (1) demonstrated xenosiderophoric activity by promoting the growth of Staphylococcus aureus , Acinetobacter baumannii , and Mycobacterium tuberculosis in iron-limited media and thus has the potential to be developed into a sideromycin against pathogens in these genera and other MDR bacteria. [Display omitted] • Sideromycins are an efficient tool against microbial resistance. • A new siderophore, serratiochelin D, is reported in this study. • Chemical structures were confirmed by extensive spectroscopic analyses. • Isolated compounds were tested for growth promoting and cytotoxic activities. [ABSTRACT FROM AUTHOR]

Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial siderophores for the active uptake by the iron acquisition system of bacteria. We synthesised two catechol-containing MBL inhibitors, as well as their dimethoxy counterparts, and tested them for in vitro inhibitory activity against NDM-1, VIM-1, and IMP-7. We demonstrated that the most potent catechol-containing MBL inhibitor is able to bind Fe3+ ions. Finally, we could show that this compound restores the antibiotic activity of imipenem in NDM-1-expressing K. pneumoniae, while leaving HUVEC cells completely unaffected. Thus, siderophore-containing MBL inhibitors might be a valuable strategy to overcome bacterial MBL-mediated resistance to beta lactam antibiotics. [ABSTRACT FROM AUTHOR]

Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial siderophores for the active uptake by the iron acquisition system of bacteria. We synthesised two catechol-containing MBL inhibitors, as well as their dimethoxy counterparts, and tested them for in vitro inhibitory activity against NDM-1, VIM-1, and IMP-7. We demonstrated that the most potent catechol-containing MBL inhibitor is able to bind Fe3+ ions. Finally, we could show that this compound restores the antibiotic activity of imipenem in NDM-1-expressing K. pneumoniae, while leaving HUVEC cells completely unaffected. Thus, siderophore-containing MBL inhibitors might be a valuable strategy to overcome bacterial MBL-mediated resistance to beta lactam antibiotics.

Sideromycins are a unique subset of siderophores comprising of a siderophore conjugated to an antimicrobial agent. The "Trojan horse" antibiotic albomycins are unique sideromycins consisting of a ferrichrome-type siderophore conjugated to a peptidyl nucleoside antibiotic. They exhibit potent antibacterial activities against many model bacteria and a number of clinical pathogens. Earlier studies have provided significant insight into the biosynthetic pathway of the peptidyl nucleoside moiety. We herein decipher the biosynthetic pathway of the ferrichrome-type siderophore in Streptomyces sp. ATCC 700974. Our genetic studies suggested that abmA, abmB, and abmQ are involved in the formation of the ferrichrome-type siderophore. Additionally, we performed biochemical studies to demonstrate that a flavin-dependent monooxygenase AbmB and an N-acyltransferase AbmA catalyze sequential modifications of L-ornithine to generate N 5 -acetyl-N 5 -hydroxyornithine. Three molecules of N 5 -acetyl-N 5 -hydroxyornithine are then assembled to generate the tripeptide ferrichrome through the action of a nonribosomal peptide synthetase AbmQ. Of special note, we found out that orf05026 and orf03299, two genes scattered elsewhere in the chromosome of Streptomyces sp. ATCC 700974, have functional redundancy for abmA and abmB, respectively. Interestingly, both orf05026 and orf03299 are situated within gene clusters encoding putative siderophores. In summary, this study provided new insight into the siderophore moiety of albomycin biosynthesis and shed light on the contingency of multiple siderophores in albomycin-producing Streptomyces sp. ATCC 700974., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Iron is a versatile redox-active catalyst and a required cofactor within a diverse array of biological processes. To almost all organisms, iron is both essential and potentially toxic, where homeostatic concentrations must be stringently maintained. Within the iron-restricted host, the survival and proliferation of microbial invaders is contingent upon exploiting the host iron pool. Bacteria express a multitude of complex, and often redundant means of acquiring iron, including surface-associated heme-uptake pathways, high affinity iron-scavenging siderophores and transporters of free inorganic iron. Within the last decade, our understanding of iron acquisition by Gram-positive pathogens has expanded substantively, from the discovery of the iron-regulated surface-determinant pathway and numerous unique siderophores through to the detailed elucidation of heme--iron extraction, and heme and siderophore coordination and transfer. This review provides a comprehensive summary of the iron acquisition strategies of notorious Gram-positive pathogens and highlights how both conserved and distinct tactics for acquiring iron contribute to the pathophysiology of these bacteria. Further, a focus on recent structural and mechanistic studies details how these iron acquisition systems may be exploited in the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Produced by bacteria, fungi and plants, siderophores are low-molecular-weight chelating agents (200-2,000 Da) to facilitate uptake of iron (Fe). They play an important role in extracellular Fe solubilization from minerals to make it available to microorganisms. Siderophores have various chemical structures and form a family of at least 500 different compounds. Some antibiotics (i.e., albomycins, ferrimycins, danomycins, salmycins, and tetracyclines) can bind Fe and some siderophores showed diverse biological activities. Functions and applications of siderophores derived from actinobacteria were reviewed to better understand the diverse metabolites. [ABSTRACT FROM AUTHOR]

There has been considerable effort expended in the investigation of the potential of siderophore conjugates of antibiotics to circumvent the permeability barrier imposed by the outer membrane of Gram-negative bacteria. There is also a small group of natural conjugates, the sideromycins. Among the synthetic analogues that have been investigated are conjugates of nucleosides, glycopeptides, macrolides, fluroquinolones, and, above all, β-lactams. Despite this effort, few compounds have progressed beyond experimental studies. One compound, the siderophore monosulfactam BAL30072, is in early clinical studies. [ABSTRACT FROM AUTHOR]

Siderophores are conditionally essential metabolites used by microbes for environmental iron sequestration. Most Streptomyces strains produce hydroxamate-based desferrioxamine (DFO) siderophores composed of repeating units of N 1 -hydroxy-cadaverine (or N 1 -hydroxy-putrescine) and succinate. The DFO biosynthetic operon, desABCD, is highly conserved in Streptomyces; however, expression of desABCD alone does not account for the vast structural diversity within this natural product class. Here, we report the in vitro reconstitution and biochemical characterization of four DesD orthologs from Streptomyces strains that produce unique DFO siderophores. Under in vitro conditions, all four DesD orthologs displayed similar saturation steady-state kinetics (V max  = 0.9-2.5 μM⋅min -1 ) and produced the macrocyclic trimer DFOE as the favored product, suggesting a conserved role for DesD in the biosynthesis of DFO siderophores. We further synthesized a structural mimic of N 1 -hydroxy-N 1 -succinyl-cadaverine (HSC)-acyl-adenylate, the HSC-acyl sulfamoyl adenosine analog (HSC-AMS), and obtained crystal structures of DesD in the ATP-bound, AMP/PP i -bound, and HSC-AMS/P i -bound forms. We found HSC-AMS inhibited DesD orthologs (IC 50 values = 48-53 μM) leading to accumulation of linear trimeric DFOG and di-HSC at the expense of macrocyclic DFOE. Addition of exogenous PP i enhanced DesD inhibition by HSC-AMS, presumably via stabilization of the DesD-HSC-AMS complex, similar to the proposed mode of adenylate stabilization where PP i remains buried in the active site. In conclusion, our data suggest that acyl-AMS derivatives may have utility as chemical probes and bisubstrate inhibitors to reveal valuable mechanistic and structural insight for this unique family of adenylating enzymes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Albomycin belongs to the class of sideromycins, compounds composed of iron carriers linked to antibiotic moieties. Albomycin was found to be active against bacteria that have a functional ferric hydroxamate transport system meaning that bacteria will actively transport albomycin until they die. We examined the activity spectrum of albomycin for bacterial pathogens and found that Enterobacteriaceae except species of Proteus and Morganella were sensitive. Resistance in the two genera was due to the lack of the ferric hydroxamate transport system. Among Gram-positive bacteria, Staphylococcus aureus and Streptococcus pneumoniae were highly sensitive, whereas Streptococcus agalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis were resistant. The in vivo efficacy of albomycin was examined in mice infected with S. pneumoniae or Yersinia enterocolitica. A single dose of 10mg albomycin/kg body weight reduced the colony-forming units of Y. enterocolitica by three to four orders of magnitude. A single dose of 1mg albomycin/kg body weight was sufficient to clear S. pneumoniae infections in mice. In direct competition experiments with wild-type S. pneumoniae and its albomycin-resistant mutant, the recovery rate of the mutant was lower than for the wild-type indicating that the mutant had reduced fitness in the mouse model. We conclude that albomycin is effective in clearing infections caused by both Gram-positive and Gram-negative bacteria in a mouse model. Albomycin treatment reduces the bacterial load allowing the immune system to remove residual albomycin-resistant bacteria, and as such would make albomycin-based antibiotics an adjunct to treatment. The ferrichrome transport system serves as a Trojan horse to get albomycin into bacteria. [Copyright &y& Elsevier]

Monocyclic β-lactams with antibiotic activity were first synthesized more than 40 years ago. Extensive early structure-activity relationship (SAR) studies, especially in the 1980s, emphasized the need for heteroatom activation of monocyclic β-lactams and led to studies of oxamazins, monobactams, monosulfactams, and monocarbams with various side chains and peripheral substitution that revealed potent activity against select strains of Gram-negative bacteria. Aztreonam, still the only clinically used monobactam, has notable activity against many Gram-negative bacteria but limited activity against some of the most problematic multidrug resistant (MDR) strains of Pseudomonas aeruginosa and Acinetobacter baumannii . Herein, we report that extension of the side chain of aztreonam is tolerated and especially that coupling of the side chain free acid with a bis-catechol siderophore mimetic significantly improves activity against the MDR strains of Gram-negative bacteria that are of most significant concern.

Background: Siderophores are small-molecule iron-chelators produced by microorganisms and plants growing mostly under low iron conditions. Siderophores allow iron capture and transport through cell membranes into the cytoplasm, where iron is released for use in biological processes. These bacterial iron uptake systems can be used for antibiotic conjugation or as targets for killing pathogenic bacteria. Siderophores have been explored recently because of their potential applications in environmental and therapeutic research. They are present in Streptomyces, Grampositive bacteria that are an important source for discovering new siderophores., Objective: This review summarizes siderophore molecules produced by the genus Streptomyces emphasizing their potential as biotechnological producers and also illustrating genomic tools for discovering siderophores useful for treating bacterial infections., Methods: The literature search was performed using PUBMED and MEDLINE databases with keywords siderophore, secondary metabolites, Trojan horse strategy, sideromycin and Streptomyces. The literature research focused on bibliographic databases including all siderophores identified in the genus Streptomyces. In addition, reference genomes of Streptomyces from GenBank were used to identify siderophore biosynthetic gene clusters by using the antiSMASH platform., Results: This review has highlighted some of the many siderophore molecules produced by Streptomyces, illustrating the diversity of their chemical structures and a wide spectrum of bioactivities against pathogenic bacteria. Furthermore, the possibility of using siderophores conjugated with antibiotics could be an alternative to overcome bacterial resistance to drugs and could improve their therapeutic efficacy., Conclusion: This review confirms the importance of Streptomyces as a rich source of siderophores, and underlines their potential as antibacterial agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multi-drug resistant infections caused by Gram-negative bacteria have become one of the most important reasons for the failure of clinical anti-infective treatment. Siderophore-antibiotic conjugates, which were designed based on a "Trojan horse" strategy wherein features enabled active uptake to bypass the Gram-negative cell wall, have been expected to be a weapon for anti-infective treatment in the clinic. Herein, we review antibiotic drug design strategies based on mimics of nature siderophores reported in recent years, we also focus our attention on the relationship between the type of linker and the corresponding antibacterial activity. Siderophore-antibiotic conjugates, which enable active uptake to bypass the Gram-negative cell wall, have been expected to be a weapon for anti-infective treatment in the clinic. Image 1 • We reviewed recent progress of studies of siderophore-antibiotic conjugates. • Drug design strategies based on nature or mimic siderophores were reviewed. • The relationship between the type of linker and the corresponding antibacterial activity are discussed. [ABSTRACT FROM AUTHOR]

Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species or strains of bacteria. The selective targeting and increased permeability and accumulation of these prodrugs not only improves efficacy over unmodified drugs but also reduces off-target effects, toxicity, and development of resistance. Herein, we discuss some of these methods, including sideromycins, antibody-directed prodrugs, cell penetrating peptide conjugates, and codrugs.

Development of resistance to antibiotics is a major medical problem. One approach to extending the utility of our limited antibiotic arsenal is to repurpose antibiotics by altering their bacterial selectivity. Many antibiotics that are used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacterial infections, if they could circumvent permeability barriers and antibiotic deactivation processes associated with Gram-negative bacteria. Herein, we report that covalent attachment of the normally Gram-positive-only antibiotic, daptomycin, with iron sequestering siderophore mimetics that are recognized by Gram-negative bacteria, provides conjugates that are active against virulent strains of Acinetobacter baumannii, including carbapenemase and cephalosporinase producers. The result is the generation of a new set of antibiotics designed to target bacterial infections that have been designated as being of dire concern.

Staphylococcus aureus produces a cocktail of metallophores (staphylopine, staphyloferrin A, and staphyloferrin B) to scavenge transition metals during infection of a host. In addition, S. aureus displays the extracellular surface lipoproteins FhuD1 and FhuD2 along with the ABC transporter complex FhuCBG to facilitate the use of hydroxamate xenosiderophores such as desferrioxamine B (DFOB) for iron acquisition. DFOB is used as a chelation therapy to treat human iron overload diseases and has been linked to an increased risk of S. aureus infections. We used a panel of synthetic DFOB analogs and a FhuD2-selective trihydroxamate sideromycin to probe xenosiderophore utilization in S. aureus and establish structure-activity relationships for Fe(III) binding, FhuD2 binding, S. aureus growth promotion, and competition for S. aureus cell entry. Fe(III) binding assays and FhuD2 intrinsic fluorescence quenching experiments revealed that diverse chemical modifications of the terminal ends of linear ferrioxamine siderophores influences Fe(III) affinity but not FhuD2 binding. Siderophore-sideromycin competition assays and xenosiderophore growth promotion assays revealed that S. aureus SG511 and ATCC 11632 can distinguish between competing siderophores based exclusively on net charge of the siderophore-Fe(III) complex. Our work provides a roadmap for tuning hydroxamate xenosiderophore scaffolds to suppress (net negative charge) or enhance (net positive or neutral charge) uptake by S. aureus for applications in metal chelation therapy and siderophore-mediated antibiotic delivery, respectively.